Serum 25-Hydroxyvitamin D and the risk of breast cancer in women from Southern Morocco: A case-control study

Abstract

OBJECTIVES:

Assessing Vitamin-D status and checking if low serum 25(OH)D is a factor in breast cancer (BC) for Southern Moroccan women.

MATERIALS/METHODS:

Study conducted in Morocco about women with BC (n = 90) and controls (n = 90). 25-hydroxy-vitamin-D biological analyzes executed during the first consultation. Social data and anthropometric parameters were collected for all participants.

RESULTS:

Women from urban areas constitued 67.78 % for the cases and 85.6% for the controls. The average age was 48.72±9.71 (cases) and 46.40±12.52 (controls). We found that 53.33% of cases and 40% of controls were postmenopausal and that hypovitaminosis-D affected 80 and 64.4% of cases and controls, respectively. Statistical analysis showed that hypovitaminosis-D was a significative risk factor for BC in Southern Moroccan women. The Odds Ratio was of 5 (p < 0.0001). The BC subtypes had Odds Ratios greater than 1. The highest value was obtained with Luminal B subtype (Odds ratio = 6.25; p = 0.0007).

CONCLUSION:

This study reinforces the evidence implicating hypovitaminosis-D among modifiable risk factors for BC. Further studies are needed to assess the extent of hypovitaminosis-D in Moroccan women with BC.

Keywords

25-HydroxyVitamin-D breast case-control study Moroccan population

1 Introduction

Globally, breast cancer (BC) is the most diagnosed cancer and the leading cause of cancer death in women. In 2020, BC represented 24.5% of new cases of cancer detected (2,261,419 cases) and 15.5% of deaths in women (684,996 cases). It is a real global health problem [1]. BC is a multifactorial pathology. Prevention of this disease requires identification of potential risk factors. Observational studies agree on the value of diet and lifestyle as a potentially modifiable risk factor for BC [2, 3]. Among nutrients, vitamin D (vit D) plays an important role in BC prevention [2]. Skin exposure to the sun, food and food supplements constitute the main sources of vit D. Vit D is present in food in two forms: vit D2 (ergocalciferol), produced mainly by plants and fungi, and vit D3 (cholecalciferol) synthetized by animal tissues. Vit D3 is mainly found in fish liver oils, certain fatty fish (salmon, sardines, herring, and mackerel), egg yolks and animals liver [4].

Association between vit D deficiency and BC was reported in many countries [5, 6]. Knowledge about the role of Vit D and its biological potential significantly evolved in recent years. It is involved in many biological processes [7, 8]. It plays an important role in the intestinal absorption of calcium and contributes to the maintenance of calcium and phosphorus homeostasis. Some studies also reported its role in the immune system, muscle and nerve functions [7, 8]. The biological potential of vit D is due to the expression of its receptor VDR (Vitamin D receptor) by most tissues in the body. VDR is related to a nuclear factor (VDR responsive element) controlling nearly 300 genes [7 –9]. Vit D has antineoplastic activities by intervening at the level of signaling pathways related to inflammation, angiogenesis, proliferation as well as cell differentiation, progression, metastases and apoptosis [10, 11]. For women especially, it improves breast health and it has anticancer activities against many cancer types, including BC [7 –9]. A healthy and balanced diet would be associated with a positive prognosis for women with BC even if their nutritional status were unfavorable [12]. Through its involvement in apoptosis of epithelial cells, Vit D deficiency is thought to be one of the risks and mortality factors of BC. There are several studies that support the association between low serum 25-hydroxy-vitamin D (25(OH)D) concentrations and the risk of BC [13, 14].

In Morocco, BC is the most common cancer in women, accounting for 38.9% of all new cancer diagnoses. This makes Morocco one of the African and Middle Eastern countries with the highest incidence from BC despite the high sunshine. This raises the question about the relationship between vit D and breast cancer in Morocco. As no study on the relationship between vit D deficiency and BC has yet been undertaken in the country, we conducted this study to assess serum 25(OH)D level in women with BC from Souss-Massa region (southern Morocco).

2 Materials and methods

2.1 Recruitment of participants

The study was conducted in 90 voluntary patients between January 2018 and June 2020. Patients were recruited randomly at the Hassan II Regional Hospital Center and at the Oncologic Regional Center of Agadir, Morocco. A set of 90 healthy voluntary women were randomly taken as controls. All participants were initially informed that their biological and anthropometric data would be exploited for scientific purposes. All participants signed and expressed consent. The study was authorized by the Moroccan Ministry of Health (authorization number 3851/02092017) and approved by Moroccan Association of Research and Ethic (MARE- N°4/REC/20). Patients were recruited according to inclusion and exclusion criteria to avoid biasing results [15 –17]. Recruitments included patients with BC without metastasis, with preoperative, postoperative, ongoing or completed treatment and no evidence of recurrence or relapse. Patients with metastatic BC and other cancers, hepatic insufficiency, renal failure, and severe psychiatric illnesses were excluded from this study. In addition, participants should not be supplemented with vit D at least 4 months before this study. The controls had no family history of BC. All participants were over 25 years old, which represents an age above the age of majority in Morocco. Controls did not take any medication. Cases followed the medical treatment prescribed by the oncologists.

2.2 Body Mass Index (BMI)

The BMI, which is calculated as the bodyweight divided by the square of height (kg/m2), was used to classify all participants into four groups according to WHO (World Health Organization) criteria [18]. The underweight was defined as BMI less than 18.5 kg/m2, normal weight as BMI between 18.5 and 24.9 kg/m2, overweight between 25 and 29.9 kg/m2, and obese had BMI equal to or greater than 30 kg/m2. A nurse performed the anthropometric assessment. The size was taken using a metal wall measuring rod of the Tanita® type. Weight and body analysis were performed by a Tanita® BC 418 MA segmental body mass analyzer. It allowed to have for each patient, the weight, the BMI. When a dichotomous classification was needed, the BMI value was used to classify the participants into two groups: overweight with BMI greater than 25 kg/m2, and normal weight corresponded to values less than 25kg/m2.

2.3 Biological determination of 25-Hydroxy-Vitamin D

Biological assay of 25(OH)D was performed during the first interview of the survey in both cases and controls. Blood sample was taken on an empty stomach by venipuncture between 7 a.m. and 9 a.m., in tubes without anticoagulant (dry tubes). The blood sample was centrifuged for 15 minutes at 3000 rpm. The supernatant was re-centrifuged for 10 min at 2000 rpm. The serum was recovered and analyzed by electrochemiluminescence technique by using anti-vitamin D antibodies on Roche Elecsys 2010 (Roche Diagnostics GmbH, Germany). The results were interpreted according to the American Society of Endocrinology which established the reference values in terms of Vit D status. Vit D deficiency is defined for serum 25(OH)D concentrations below 20 ng/mL. (50 nmol/L), while insufficiency is attributed to concentrations between 21 and 29 ng/mL (52–72 nmol/L) and any concentration above 30 ng/mL (75 nmol/L) is considered to be sufficient [19].

2.4 Molecular subtypes

The cases of BC were classified as molecular subtypes by the medical team based on the expert report of the 13th International Breast Cancer Conference (St. Gallen, Switzerland, 2013) [20]. This classification refers to the expression of hormone receptors and to the tumor and proliferative marker Ki67 (luminal A (ER+ and / or PR+, HER2–); luminal B (ER+ and / or PR+, HER2+); HER2 positive (ER-, PR–, HER2+) and triple negative (ER–, PR–, HER2–).

2.5 Statistical analysis

Quantitative variables were reported as mean±standard deviation, while qualitative variables were reported as percentages. Student’s “t” test was performed to compare characteristics between cases and controls, and the chi-square test to compare qualitative variables. We considered P values less than or equal to 0.05 to be statistically significant. All statistical analysis were performed with SPSS software version 20.0 (statistical software SPSS Inc., Chicago IL., USA).

3 Results

The Social and anthropometric data of the participants are shown in Table 1. Women from rural areas represented 32.22% of the cases and 14.4% of the controls. Regarding marital status, single and divorced women represented for each a percentage of 13.33% or 26.66% in total for the cases, while the percentage of brides and widows were 57.78% and 15.56% respectively. In the control group, celibates and widows represented 2.22% and 2.22%, while the percentages of married and divorced were 91.11% and 4.44% respectively.

Table 1
Social and anthropometric data of the participants

Controls (n = 90) Cases (n = 90)

Marital status Single 2 (2.22%) 12 (13.33%)

Divorced 4 (4.44%) 12 (13.33%)

Married 82 (91.11%) 52 (57.78%)

Widow 2 (2.22%) 14 (15.55%)

Age 46.40±12.52 48.72±9.71 (p = 0.16)

Parity 2.82±1.7 2.71±1.87 (p = 0.63)

BMI 29.05±3.60 28.40±4.96 (p = 0.31)

		Controls (n = 90)	Cases (n = 90)
Marital status	Single	2 (2.22%)	12 (13.33%)
	Divorced	4 (4.44%)	12 (13.33%)
	Married	82 (91.11%)	52 (57.78%)
	Widow	2 (2.22%)	14 (15.55%)
Age	46.40±12.52	48.72±9.71 (p = 0.16)
Parity	2.82±1.7	2.71±1.87 (p = 0.63)
BMI	29.05±3.60	28.40±4.96 (p = 0.31)

BMI: body mass index.

Tumors were classified according to the BC phenotypes. Figure 1 shows that 41% of the patients had luminal A, 36% had luminal B, 10% had HER and 13% had triple negative phenotype.

Fig. 1

Case distribution by molecular subtype of Breast Cancer.

The mean age was no significantly different between cases and controls (48.72 and 46.40 years respectively). Similarly, rates of menopausal women in cases (53.33%) and controls (40%) were not significantly different. The mean number of children for each woman was 2.71 and 2.82 respectively in the cases and the controls without significant difference.

Controls and cases had an average weight of 68.36 and 72.44 Kg respectively. Participants had an average BMI of 28.40 kg/m2 for cases and 29.05 kg/m2 for controls without a significant difference.

Table 2 shows serum vit D in patients and controls. The mean level was significantly lower (p < 0.0001) in the cases (17.00 ng/ml) compared to controls (22.57 ng/ml). Women with hypovitaminosis D depicted 80% and 44.44% in cases and controls respectively (Fig. 2). The results showed that BC patients had significantly lower serum Vit D levels than controls (p < 0.0001). We did not notice any significant difference when we compared serum Vit D levels in the molecular subtypes of BC in cases group (Table 2). However, by comparing the different molecular subtypes with the controls, the degrees of significance were different depending on each subtype. Luminal B and HER showed the lowest values.

Table 2

Serum vitamin D in patients with different subtypes of breast cancer compared to controls

	Mean±SD (ng / mL)	p-Value
Controls	22.57±10.95	–
Total Cases (n = 90)	17.00±8.65	< 0.001
Luminal A	18.13±12.02	0.052
Luminal B	16.45±4.54	< 0.001
Triple negative	16.19±5.48	0.003
HER	14.66±4.06	< 0.001

Fig. 2

Classification of cases and controls according to their vitamin D status.

Table 3 reports the odds ratio (OR) of cases and BC subtypes compared to controls. Values were of 5 for cases (p < 0.0001). The subtypes of BC recorded different ORs. Luminal B had the highest value (OR = 6.25). It was followed by luminal A (OR = 4.2), triple negative (OR = 3.75) and HER (OR = 2).

Table 3

Odds ratio of cases and breast cancer subtypes compared to controls

	Odds ratio	Confidence interval (95 %)		p-Value
Total cases	5	2.6	9.7	< 0.0001
Luminal A	4.22	1.77	9.78	0.0007
Luminal B	6.25	2.2	17.8	0,0002
Triple negative	3.75	0.95	14.77	0.047
HER	2	1.44	2.77	Nd

Nd: not determined (because of the limited number of the HER subtype cases).

4 Discussion

As BC has a high incidence in Morocco despite the strong sunshine, we aim from this study to check if hypovitaminosis D is a risk factor for BC in women from southern Morocco. The results showed that Moroccan women with BC had a significantly lower Vit D level than the control group. This was true for all BC subtypes. The risk factors were between 2 and 6.25 for the different subtypes with a value of 5 for all cases. These results are in accordance with other case-control studies performed in other countries, which reported an inverse association between serum 25(OH)D levels and the risk of BC. In 2013, an Australian study on 214 newly diagnosed BC patients and 852 controls showed that adequate serum 25(OH)D levels were inversely associated with BC risk (OR = 2.3, p < 0.001) [21]. Similar results were reported by case-control studies in India and Saudi Arabia. The Indian study [22] which included 200 women (100 cases and 100 controls) revealed a significant association between low serum 25(OH)D and BC risk (OR = 2.5). For the Saudi study [23], women with BC had significantly lower serum Vit D concentrations than controls (p = 0.001). The serum concentration of 25(OH)D less than 20 (ng/mL) was associated with a high risk of BC (OR = 6.1, p = 0.0001). However, another case-control study found this risk only in premenopausal women, but not in postmenopausal women [24]. Our results also concurred with those of a meta-analysis that examined the association between hypovitaminosis D and BC risk [25]. This meta-analysis grouped six case-control studies into a total of 7031 women (3,250 cases and 3,781 controls). It concluded at OR = 2.49 (P < 0.001). Three other more recent Meta-analyzes showed that Vit D deficiency was associated with an increased risk of BC [26 –28]. In a recent cohort study, McDonnell et al. reported that the BC incidence rate was 82% lower in women with serum 25(OH)D concentrations over 60 (ng/mL) than in those with levels below 20 (ng/mL) [29].

The proportion of women from urban areas was significantly higher than in our study. This may influence the outcome of our study as we were aware that compared to women from rural areas, women from urban areas are more attentive to preventive health messages and have easier access to health care. Also, from the diagnosis of BC, women’s eating habits change radically, eliminating all animal and Vit D fortified products [30]. Based on the comparisons between the molecular subtypes of the cases compared to all the controls, it appears that the luminal B subtype is more affected by vit D deficiency followed by the HER subtype and luminal A. These results conform in part to those reported by Kim et al. [31]. However, another meta-analysis suggested that low vit D status may increase the risk of BC, especially triple-negative BC [32]. In view of the importance of the proportions of these subtypes in our sample and the unfavorable prognosis which was observed in the study cited above, the anticipation of problem of hypovitaminosis D is necessary.

During nutritional interviews, Moroccan women with BC declared they eliminated meat, liver and fatty fish from their diet. However, these foods are a source of Vit D [33]. For fear of questions about their disease, some Moroccan women with BC refrained from going out and outdoor activities, already very low among Moroccan women. In addition, we noted the effect of social networks and pseudo-scientific ideas on behavior changes and the onset of certain food aversions among Moroccan women with BC.

This study presented some limitations, mainly inability to control individual factors that are known to affect vit D status such as dress style, sun exposure, skin pigmentation, supplements, and vitamin intake from food. However, this first study carried out on women from North Africa characterized by high sunshine, allows us to conclude that there is a greater risk of BC for the luminal A and luminal B subtypes, unlike previous work which reports a greater risk for the HER and TN subtypes (Laporta and Welsh, 2014; Yao and Ambrosone, 2013 for example) [34, 35]. This requires further investigations to elucidate the origin of this difference.

5 Conclusion

This is the first case-control study conducted to investigate the relationship between BC and vit D status in Moroccan women. Like most studies, the present work shows that low serum 25(OH)D concentrations are strongly associated with an increased risk of BC. Based on this finding, the management of BC patients should incorporate nutritional counseling that encourages the use of vit D for the prevention and the treatment of BC. Vit D is an inexpensive nutrient that is easy to access and use. In addition, randomized clinical trials are needed to confirm the role of vit D in the management of BC. Thus, sun exposure and/or Vit D supplementation at adequate doses are recommended to reduce the risk of BC.

Footnotes

Acknowledgments

The authors would like to acknowledge:

The Regional Director of Public Health of Souss Massa, medical, nursing and administrative staff of the Regional Center of Oncology of Souss Massa and the Gynecology Department of Hassan II Regional Hospital Center of Agadir.

Dr. Miriam Dwek, Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.

Abdelmajid Ridouane Associate Professor Educational English Coordinator at the Higher School of Education and Training Ibn Zohr University, Agadir- Morocco.

Financial support and sponsorship

The authors report no funding.

Conflicts of interest

The authors have no conflict of interest to report.

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